Our goal is to reach a better understanding of the mechanisms of intracellular protein degradation. We have shown that the thermal stability of lysozyme increases with increasing concentrations of tri-N-acetylglucosamine, a trisaccharide which binds specifically at the active site of native lysozyme. The stability enhancement can be predicted if the equilibrium constant for binding of the substrate to the enzyme is known. Thus, the increased stability of an enzyme in the presence of its substrate, coenzyme, or any small molecule that it bonds specifically results because binding to the native state shifts the unfolding equilibrium and decreases the concentration of unfolded states of the enzyme. It is suggested that this may be a more important factor than substrate-induced conformational changes in accounting for the decreased rates of protein catabolism frequently observed in vivo at elevated substrate concentrations.